Omega chain modified 15-hydroxyeicosatetraenoic acid derivatives and methods of their use for the treatment of dry eye

ABSTRACT

Omega chain modified 15-HETE derivatives and methods of their use for treating dry eye are disclosed.

[0001] This application claims priority to co-pending U.S. ProvisionalApplications, Serial No. 60/164,375 filed Nov. 9, 1999, and 60/211,587,filed Jun. 15, 2000.

[0002] The present invention is directed to compositions containingcertain 15-hydroxyeicosatetraenoic acid derivatives and methods fortheir use in treating dry eye.

BACKGROUND OF THE INVENTION

[0003] Dry eye, also known generically as keratoconjunctivitis sicca, isa common ophthalmological disorder affecting millions of Americans eachyear (Schein et. al., Prevalence of dry eye among the elderly. AmericanJ. Ophthalmology, 124:723-738, (1997)). The condition is particularlywidespread among post-menopausal women due to hormonal changes followingthe cessation of fertility. Dry eye may afflict an individual withvarying severity. In mild cases, a patient may experience burning, afeeling of dryness, and persistent irritation such as is often caused bysmall bodies lodging between the eye lid and the eye surface. In severecases, vision may be substantially impaired. Other diseases, such asSjogren's disease and cicatricial pemphigoid manifest dry eyecomplications.

[0004] Although it appears that dry eye may result from a number ofunrelated pathogenic causes, all presentations of the complication sharea common effect, that is the breakdown of the pre-ocular tear film,which results in dehydration of the exposed outer surface and many ofthe symptoms outlined above (Lemp, Report of the Nation EyeInstitute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAOJournal, volume 21, number 4, pages 221-231 (1995)). Four events havebeen identified which singly or in combination are believed to result inthe dry eye condition: a) decreased tear production or increased tearevaporation; b) decreased conjunctival goblet-cell density; c) increasedcorneal desquamation; and d) destabilization of the cornea-tearinterface (Gilbard, Dry eye: pharmacological approaches, effects, andprogress. The CLAO Journal, (22:141-145 (1996)). Another major problemis the decreased mucin production by the conjunctival cells and/orcorneal epithelial cells of mucin, which protects and lubricates theocular surface (Gipson and Inatomi, Mucin genes expressed by ocularsurface epithelium. Progress in Retinal and Eye Research, 16:81-98(1997)).

[0005] Practitioners have taken several approaches to the treatment ofdry eye. One common approach has been to supplement and stabilize theocular tear film using so-called artificial tears instilled throughoutthe day. Another approach has been the use of ocular inserts thatprovide a tear substitute or to stimulate endogenous tear production.

[0006] Examples of the tear substitution approach include the use ofbuffered, isotonic saline solutions, aqueous solutions containing watersoluble polymers that render the solutions more viscous and thus lesseasily shed by the eye. Tear reconstitution is also attempted byproviding one or more components of the tear film such as phospholipidsand oils. Examples of these treatment approaches are disclosed in U.S.Pat. Nos. 4,131,651 (Shah et al.), 4,370,325 (Packman), 4,409,205(Shively), 4,744,980 and 4,883,658 (Holly), 4,914,088 (Glonek),5,075,104 (Gressel et al.) and 5,294,607 (Glonek et al.).

[0007] United States Patents directed to the use of ocular inserts inthe treatment of dry eye include U.S. Pat. No. 3,991,759 (Urquhart).Other semi-solid therapy has included the administration of carrageenans(U.S. Pat. No. 5,403,841, Lang) which gel upon contact with naturallyoccurring tear film.

[0008] Another recent approach involves the provision of lubricatingsubstances in lieu of artificial tears. U.S. Pat. No. 4,818,537 (Guo)discloses the use of a lubricating, liposome-based composition.

[0009] Aside from the above efforts, which are directed primarily to thealleviation of symptoms associated with dry eye, methods andcompositions directed to treatment of the dry eye condition have alsobeen pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) disclosesthe use of sex steroids, such as conjugated estrogens, to treat dry eyecondition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen)discloses the use of finely divided calcium ion compositions tostimulate preocular tear film; and U.S. Pat. No. 4,966,773 (Gressel etal.) discloses the use of microfine particles of one or more retinoidsfor ocular tissue normalization.

[0010] Although these approaches have met with some success, problems inthe treatment of dry eye nevertheless remain. The use of tearsubstitutes, while temporarily effective, generally requires repeatedapplication over the course of a patient's waking hours. It is notuncommon for a patient to have to apply artificial tear solution ten totwenty times over the course of the day. Such an undertaking is not onlycumbersome and time consuming, but is also potentially very expensive.Transient symptoms of dry eye associated with refractive surgery havebeen reported to last in some cases from six weeks to six months or morefollowing surgery.

[0011] The use of ocular inserts is also problematic. Aside from cost,they are often unwieldy and uncomfortable. Further, as foreign bodiesintroduced in the eye, they can be a source of contamination leading toinfections. In situations where the insert does not itself produce anddeliver a tear film, artificial tears must still be delivered on aregular and frequent basis.

[0012] In view of the foregoing, there is a clear need for an effectivetreatment for dry eye that is capable of alleviating symptoms, as wellas treating the underlying physical and physiological deficiencies ofdry eye, and that is both convenient and inexpensive to administer.

[0013] Mucins are proteins which are heavily glycosylated withglucosamine-based moieties. Mucins provide protective and lubricatingeffects to epithelial cells, especially those of mucosal membranes.Mucins have been shown to be secreted by vesicles and discharged on thesurface of the conjuctival epithelium of human eyes (Greiner et al.,Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers ofContact Lenses, Archives of Ophthalmology, volume 98, pages 1843-1846(1980); and Dilly et al., Surface Changes in the Anaesthetic Conjunctivain Man, with Special Reference to the Production of Mucus from aNon-Goblet-Cell Source, British Journal of Ophthalmology, volume 65,pages 833-842 (1981)). A number of human-derived mucins which reside inthe apical and subapical corneal epithelium have been discovered andcloned (Watanabe et al., Human Corneal and Conjuctival Epithelia Producea Mucin-Like Glycoprotein for the Apical Surface, InvestigativeOphthalmology and Visual Science, volume 36, number 2, pages 337-344(1995)). Recently, Watanabe discovered a new mucin which is secreted viathe cornea apical and subapical cells as well as the conjunctivalepithelium of the human eye (Watanabe et al., IOVS, volume 36, number 2,pages 337-344 (1995)). These mucins provide lubrication, andadditionally attract and hold moisture and sebacious material forlubrication and the corneal refraction of light.

[0014] Mucins are also produced and secreted in other parts of the bodyincluding lung airway passages, and more specifically from goblet cellsinterspersed among tracheal/bronchial epithelial cells. Certainarachidonic acid metabolites have been shown to stimulate mucinproduction in these cells. Yanni reported the increased secretion ofmucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid(“HETE”) derivatives (Yanni et al, Effect of Intravenously AdministeredLipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness,International Archives of Allergy And Applied Immunology, volume 90,pages 307-309 (1989)). Similarly, Marom has reported the production ofmucosal glycoproteins in human lung by HETE derivatives (Marom et al.,Human Airway Monohydroxy-eicosatetraenoic Acid Generation and MucusRelease, Journal of Clinical Investigation, volume 72, pages 122-127(1983)). Nowhere in the art, however, has the use of HETE derivativesbeen proposed to stimulate mucin production in ocular tissues as atreatment for dry eye.

[0015] The conventional treatment for dry eye, as discussed above,includes administration of artificial tears to the eye several times aday. Other agents claimed for increasing ocular mucin and/or tearproduction include vasoactive intestinal polypeptide (Dartt et. al.,Vasoactive intestinal peptide-stimulated glycocongiugate secretion fromconjunctival goblet cells. Experimental Eye Research, 63:27-34, (1996)), gefarnate (Nakmura et. al., Gefarnate stimulates secretion ofmucin-like glycoproteins by corneal epithelium in vitro and protectscorneal epithelium from dessication in vivo, Experimental Eye Research,65:569-574 (1997)), and the use of liposomes (U.S. Pat. No. 4,818,537),androgens (U.S. Pat. No. 5,620,921), melanocycte stimulating hormones(U.S. Pat. No. 4,868,154), and phosphodiesterase inhibitors (U.S. Pat.No. 4,753,945), retinoids (U.S. Pat. No. 5,455,265). However, many ofthese compounds or treatments suffer from a lack of specificity,efficacy and potency and none of these agents have been marketed so faras therapeutically useful products to treat dry eye and related ocularsurface diseases. Of particular relevance to the present invention isthe claimed use of hydroxyeicosatetraenoic acid derivatives to treat dryeye (U.S. Pat. No. 5,696,166). Thus, there remains a need for anefficacious therapy for the treatment of dry eye and related diseases.

SUMMARY OF THE INVENTION

[0016] The present invention is directed to compositions and methods forthe treatment of dry eye and other disorders requiring the wetting ofthe eye, including symptoms of dry eye associated with refractivesurgery such as LASIK surgery. More specifically, the present inventiondiscloses derivatives of(5Z,8Z,11Z,13E)-15-hydroxyeicosa-5,8,11,14-tetraenoic acid (15-HETE) inwhich the ω-chain is modified as to inhibit metabolic oxidation at C-15,and methods using the same for treating dry eye type disorders. Thecompositions are preferably administered topically to the eye.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The ω-chain modified 15-HETE derivatives of the present inventionare those of formula I:

[0018] wherein:

[0019] R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where:

[0020] R is H or a pharmaceutically acceptable cation, or CO₂R forms apharmaceutically acceptable ester moiety;

[0021] NR²R³, NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group;

[0022] OR⁴ comprises a free or functionally modified hydroxy group;

[0023] Hal is F, Cl, Br, or;

[0024] SR²⁰ comprises a free or functionally modified thiol group;

[0025] R²¹ is H or a pharmaceutically acceptable cation, or COSR²¹ formsa pharmaceutically acceptable thioester moiety;

[0026] A, B, C, D are the same or different and are C₁-C₅ alkyl, C₂-C₅alkenyl, C₁₋₅ cyclopropyl, C₂-C₅ alkynyl, or a C₃-C₅ allenyl group;

[0027] E is

[0028] where OR⁷ comprises a free or functionally modified hydroxygroup;

[0029] X=(CH₂)_(m) or (CH₂)_(m)O, where m=1-6; and

[0030] Y=a phenyl ring optionally substituted with alkyl, halo,trihalomethyl, acyl, or a free or functionally modified hydroxy, amino,or thiol group; or

[0031] X—Y=(CH₂)_(p)Y¹; where p=0-6; and

[0032] wherein:

[0033] W=CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q), CH═N,or CH₂NR⁸; where q=0-2, and R⁸=H, alkyl, or acyl;

[0034] Z═H, alkyl, acyl, halo, trihalomethyl, or a free or functionallymodified amino, thiol, or hydroxy group; and

[0035] - - - =single or double bond;

[0036] or X—Y=cyclohexyl.

[0037] To the best of our knowledge none of the compounds of the presentinvention have been previously reported in the literature.

[0038] Included within the scope of the present invention are theindividual enantiomers of the title compounds, as well as their racemicand non-racemic mixtures. The individual enantiomers can beenantioselectively synthesized from the appropriate enantiomericallypure or enriched starting material by means such as those describedbelow. Alternatively, they may be enantioselectively synthesized fromracemic/non-racemic or achiral starting materials. (AsymmetricSynthesis; J. D. Morrison and J. W. Scott, Eds.; Academic PressPublishers: New York, 1983-1985, volumes 1-5; Principles of AsymmetricSynthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers:Amsterdam, 1996). They may also be isolated from racemic and non-racemicmixtures by a number of known methods, e.g. by purification of a sampleby chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G.Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations byHPLC; A. M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or byenantioselective hydrolysis of a carboxylic acid ester sample by anenzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1(1989)). Those skilled in the art will appreciate that racemic andnon-racemic mixtures may be obtained by several means, including withoutlimitation, nonenantioselective synthesis, partial resolution, or evenmixing samples having different enantiomeric ratios. Departures may bemade from such details within the scope of the accompanying claimswithout departing from the principles of the invention and withoutsacrificing its advantages. Also included within the scope of thepresent invention are the individual isomers substantially free of theirrespective enantiomers.

[0039] As used herein, the terms “pharmaceutically acceptable cationicsalt”/“pharmaceutically acceptable ester moiety/pharmaceuticallyacceptable thioester moiety” means any cationic salt/ester/thioestermoiety that would be suitable for therapeutic administration to apatient by any conventional means without significant deleterious healthconsequences; and “ophthalmically acceptable cationicsalt”/“ophthalmically acceptable ester/ophthalmically acceptablethioester moiety” means any pharmaceutically acceptable cationicsalt/ester/thioester moiety that would be suitable for ophthalmicapplication, i.e. non-toxic and non-irritating. Wavy line attachmentsindicate that the configuration may be either alpha (α) or beta (β).Hatched lines indicate the a configuration. A solid triangular lineindicates the β configuration.

[0040] The term “free hydroxy group” means an OH. The term “functionallymodified hydroxy group” means an OH which has been functionalized toform: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl,alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl groupis substituted for the hydrogen; an ester, in which an acyl group issubstituted for the hydrogen; a carbamate, in which an aminocarbonylgroup is substituted for the hydrogen; or a carbonate, in which anaryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, oralkynyloxycarbonyl group is substituted for the hydrogen. Preferredmoieties include OH, OCH₂C(O)CH₃,OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,and OC(O)C₂H₅.

[0041] The term “free amino group” means an NH₂. The term “functionallymodified amino group” means an NH₂ which has been functionalized toform: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-,alkynyl, or hydroxyamino group, where the appropriate group issubstituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-,cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-,heterocycloalkenyl-, or alkynylamino group, where the appropriate groupis substituted for one or both of the hydrogens; an amide, in which anacyl group is substituted for one of the hydrogens; a carbamate, inwhich an an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, oralkynylcarbonyl group is substituted for one of the hydrogens; or aurea, in which an aminocarbonyl group is substituted for one of thehydrogens. Combinations of these substitution patterns, for example anNH₂ in which one of the hydrogens is replaced by an alkyl group and theother hydrogen is replaced by an alkoxycarbonyl group, also fall underthe definition of a functionally modified amino group and are includedwithin the scope of the present invention. Preferred moieties includeNH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, NHC(O)CH₃, NHOH, and NH(OCH₃).

[0042] The term “free thiol group” means an SH. The term “functionallymodified thiol group” means an SH which has been functionalized to form:a thioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl,alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl groupis substituted for the hydrogen; or a thioester, in which an acyl groupis substituted for the hydrogen. Preferred moieities include SH,SC(O)CH₃, SCH₃, SC₂H₅, SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃.

[0043] The term “acyl” represents a group that is linked by a carbonatom that has a double bond to an oxygen atom and a single bond toanother carbon atom.

[0044] The term “alkyl” includes straight or branched chain aliphatichydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Thealkyl groups may be interrupted by one or more heteroatoms, such asoxygen, nitrogen, or sulfur, and may be substituted with other groups,such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy.Preferred straight or branched alkyl groups include methyl, ethyl,propyl, isopropyl, butyl and t-butyl.

[0045] The term “cycloalkyl” includes straight or branched chain,saturated or unsaturated aliphatic hydrocarbon groups which connect toform one or more rings, which can be fused or isolated. The rings may besubstituted with other groups, such as halogen, hydroxyl, aryl, aryloxy,alkoxy, or lower alkyl. Preferred cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

[0046] The term “C₁- C₅ cyclopropyl” means an alkyl chain of 1 to 5carbon atoms containing a cyclopropyl group wherein the cyclopropylgroup may start, be contained in or terminate the alkyl chain.

[0047] The term “heterocycloalkyl” refers to cycloalkyl rings thatcontain at least one heteroatom such as O, S, or N in the ring, and canbe fused or isolated. The rings may be substituted with other groups,such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl.Preferred heterocycloalkyl groups include pyrrolidinyl,tetrahydrofuranyl, piperazinyl, and tetrahydropyranyl.

[0048] The term “alkenyl” includes straight or branched chainhydrocarbon groups having 1 to 15 carbon atoms with at least onecarbon-carbon double bond, the chain being optionally interrupted by oneor more heteroatoms. The chain hydrogens may be substituted with othergroups, such as halogen. Preferred straight or branched alkeny groupsinclude, allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

[0049] The term “cycloalkenyl” includes straight or branched chain,saturated or unsaturated aliphatic hydrocarbon groups which connect toform one or more non-aromatic rings containing a carbon-carbon doublebond, which can be fused or isolated. The rings may be substituted withother groups, such as halogen, hydroxyl, alkoxy, or lower alkyl.Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl.

[0050] The term “heterocycloalkenyl” refers to cycloalkenyl rings whichcontain one or more heteroatoms such as O, N, or S in the ring, and canbe fused or isolated. The rings may be substituted with other groups,such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl.Preferred heterocycloalkenyl groups include pyrrolidinyl,dihydropyranyl, and dihydrofuranyl.

[0051] The term “carbonyl group” represents a carbon atom double bondedto an oxygen atom, wherein the carbon atom has two free valencies.

[0052] The term “aminocarbonyl” represents a free or functionallymodified amino group bonded from its nitrogen atom to the carbon atom ofa carbonyl group, the carbonyl group itself being bonded to another atomthrough its carbon atom.

[0053] The term “lower alkyl” represents alkyl groups containing one tosix carbons (C₁-C₆).

[0054] The term “halogen” represents fluoro, chloro, bromo, or iodo.

[0055] The term “aryl” refers to carbon-based rings which are aromatic.The rings may be isolated, such as phenyl, or fused, such as naphthyl.The ring hydrogens may be substituted with other groups, such as loweralkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc.Preferred aryl groups include phenyl, 3-(trifluoromethyl)phenyl,3-chlorophenyl, and 4-fluorophenyl.

[0056] The term “heteroaryl” refers to aromatic hydrocarbon rings whichcontain at least one heteroatom such as O, S, or N in the ring.Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with8 to 10 atoms. The heteroaryl ring(s) hydrogens or heteroatoms with openvalency may be substituted with other groups, such as lower alkyl orhalogen. Examples of heteroaryl groups include imidazole, pyridine,indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline,dihydrobenzofuran, and dihydrobenzindole.

[0057] The terms “aryloxy”, “heteroaryloxy”, “alkoxy”, “cycloalkoxy”,“heterocycloalkoxy”, “alkenyloxy”, “cycloalkenyloxy”,“heterocycloalkenyloxy”, and “alkynyloxy” represent an aryl, heteroaryl,alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,heterocycloalkenyl, or alkynyl group attached through an oxygen linkage.

[0058] The terms “alkoxycarbonyl”, “aryloxycarbonyl”,“heteroaryloxycarbonyl”, “cycloalkoxycarbonyl”,“heterocycloalkoxycarbonyl”, “alkenyloxycarbonyl”,“cycloalkenyloxycarbonyl”, “heterocycloalkenyloxycarbonyl”, and“alkynyloxycarbonyl” represent an alkoxy, aryloxy, heteroaryloxy,cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy,heterocycloalkenyloxy, or alkynyloxy group bonded from its oxygen atomto the carbon of a carbonyl group, the carbonyl group itself beingbonded to another atom through its carbon atom.

[0059] Preferred compounds of the present invention include those offormula I, wherein:

[0060] R¹ is CO₂R, where R is H or an ophthalmically acceptable cationicsalt, or CO₂R forms an ophthalmically acceptable ester moiety;

[0061] A, B, C, D are the same or different and are CH₂CH₂, CH═CH, C≡C,or

[0062] E is

[0063] where R⁷ is H or CH₃;

[0064] X is CH₂CH₂ or CH₂O; and

[0065] Y phenyl, optionally substituted with halo, trifluoromethyl, or afree or functionalized hydroxy group; or

[0066] X—Y=cyclohexyl; or

[0067] X—Y=Y¹,

[0068] Among the especially preferred of the foregoing are compounds1-4, whose preparations are detailed in the following examples 1-4:

EXAMPLE 1:

[0069]

[0070] (5Z, 11Z,13E)-(15RS)-15-hydroxy-16-phenoxy-17,18,19,20-tetranoreicosa-5,11,13-trienoicacid (1)

[0071] Treatment of phenol with potassium carbonate andbromoacetaldehyde diethyl acetal provides phenoxyacetaldehyde diethylacetal. Treatment with aqueous HCl followed by addition of theintermediate aldehyde to a −78° C. solution of ethynyl lithium affordsalkyne 5. Treatment of 1-hexyne (6) with n-BuLi and paraformaldehydeaffords an intermediate propargyl alcohol, which is treated sequentiallywith KH/1,3-diaminopropane and I₂/morpholine to afford iodoalkyne 7.Reduction of 7 with dipotassium azodicarboxylate/acetic acid in methanolprovides the cis-vinyl iodide 8. Palladium-catalyzed coupling of 8 andpropargyl alcohol 5 gives enynediol 9. Reduction of 9 with LiAlH₄ yieldsdiol 10, which is oxidized to aldehyde 11 using catalytic2,2,6,6-tetramethylpiperidinoxyl free radical (TEMPO) and stoichiometricN-chlorosuccinimide (NCS). Wittig condensation of 11 with(4-carboxybutyl)triphenylphosphonium bromide in the presence ofpotassium t-butoxide (KOBu^(t)) affords 1.

EXAMPLE 2:

[0072]

[0073](5Z,11Z)-(15RS)-15-hydroxy-16-phenoxy-17,18,19,20-tetranoreicosa-5,11-dien-13-ynoicacid (2)

[0074] Oxidation of diol 9 with catalytic TEMPO/stoichiometric NCSprovides aldehyde 12, which is condensed with4-(carboxybutyl)triphenylphosphonium bromide n the presence of KOBu^(t)to afford 2.

EXAMPLE 3:

[0075]

[0076](5Z,11Z)-(15RS)-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanoreicosa-5,11-dien-13-ynoicacid (3)

[0077] Addition of cyclohexanecarboxaldehyde to a −78° C. solution ofethynyllithium provides alkynol 13, which is coupled with vinyl iodide 8under Sonogashira conditions [catalytic PdCl₂(PPh₃)₂, catalytic Cul,Et₂NH) to give enyne 14. Oxidation of 14 with catalyticTEMPO/stoichiometric NCS yields aldehyde 15, which is condensed with4-(carboxybutyl)triphenylphosphonium bromide in the presence of KOBu^(t)to afford 3.

EXAMPLE 4:

[0078]

[0079](5Z,11Z,13E)-(15RS)-15-cyclohexyl-15-hydroxyeicosa-5,11,13-trienoic acid(4)

[0080] Reduction of enyne 14 with LiAlH₄ affords diene 16, which isoxidized to aldehyde 17 using catalytic TEMPO/stoichiometric NCS. Wittigcondensation of 17 with 4-(carboxybutyl)triphenylphosphonium bromide inthe presence of KOBu^(t) affords 4.

[0081] The compounds of the present invention may be contained invarious types of pharmaceutical compositions, in accordance withformulation techniques known to those skilled in the art. Preferably,these compounds will be formulated in solutions for topical ophthalmicadministration. The level of peroxy compounds in the HETE derivative rawmaterials that are used to prepare the pharmaceutical formulations ofthe present invention may have an impact on the HETE derivative'sbiological activity. Although the precise relationship has not beendefined, it is preferable to use HETE derivative raw material suppliescontaining peroxy compounds at levels no greater than about 0.3 ppm.Methods for determining peroxy levels are known in the art (e.g.,European Pharmacopoeia 1997 3^(rd) Ed., Method 2.5.5—Peroxide Value).

[0082] The ophthalmic compositions of the present invention will includeone or more compounds of the present invention in a pharmaceuticallyacceptable vehicle. Various types of vehicles may be used. Aqueoussolutions are generally preferred, based on ease of formulation,biological compatibility, as well as a patient's ability to easilyadminister such compositions by means of instilling one to two drops ofthe solutions in the affected eyes. However, the compounds of thepresent invention may also be readily incorporated into other types ofcompositions, such as suspensions, viscous or semi-viscous gels, orother types of solid or semi-solid compositions. Suspensions may bepreferred for those compounds of the present invention which are lesssoluble in water. The ophthalmic compositions of the present inventionmay also include various other ingredients, such as buffers,preservatives, co-solvents and viscosity building agents.

[0083] An appropriate buffer system (e.g., sodium phosphate, sodiumacetate or sodium borate) may be added to prevent pH drift under storageconditions.

[0084] Antioxidants may be added to compositions of the presentinvention to protect the active ingredients from oxidation duringstorage. Examples of such antioxidants include vitamin E and analogsthereof, ascorbic acid and butylated hydroxytoluene (BHT).

[0085] Ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethylalcohol, edetate disodium, sorbic acid, polyquaternium-1, or otheragents known to those skilled in the art. Such preservatives aretypically employed at a level of from 0.001 to 1.0% weight/volume (“%w/v”).

[0086] In general, the doses used for the above described purposes willvary, but will be in an effective amount to increase mucin production inthe eye and thus eliminate or improve dry eye conditions. As usedherein, the term “pharmaceutically effective amount” refers to an amountwhich improves the dry eye condition in a human patient. When thecompositions are dosed topically, they will generally be in aconcentration range of from 0.001 to about 1.0% w/v, with 1-2 dropsadministered 1-4 times per day.

[0087] As used herein, the term “pharmaceutically acceptable carrier”refers to any vehicle which, when formulated, is safe, and provides theappropriate delivery for the desired route of administration of aneffective amount of at least one compound of the present invention.

[0088] In one embodiment, the ophthalmic compositions of the presentinvention will contain ethanol in addition to a compound of formula (I).As used herein, “an effective concentration of ethanol” refers to aconcentration that enhances the biological efficacy of the formula (I)compositions in vivo. In general, the concentration of ethanol necessaryfor the enhancement of the compounds of formula (I) is believed to besomewhat proportional to the concentration of the formula (I)compound(s) administered. If a relatively high concentration of formula(I) compound(s), e.g., above 0.01% w/v, is administered, theconcentration of ethanol in such compositions may be proportionally lessthan analogous compositions containing lower concentrations of formula(I) compounds. In general, however, the ethanol concentration containedin the ophthalmic compositions of the present invention will range fromabout 0.001-2% w/v. Compositions containing formula (1) concentrationsof about 0.00001-0.02% w/v preferably will contain ethanol in aconcentration of about 0.005-0.2% w/v, and most preferably, about0.02-0.10% w/v. An example of a topically administrable ophthalmicformulation according to this embodiment of the present invention isprovided below.

EXAMPLE 5

[0089] Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.01Ethanol 0.0505 Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium Chloride0.75 Disodium Edetate 0.01 Polyquaternium-1 0.001 NaOH/HCl q.s., pH =7.5 Purified Water q.s. 100%

[0090] The above composition is prepared by the following method. Thebatch quantities of polyoxyl 40 stearate, boric acid, sodium chloride,disodium edetate, and polyquaternium-1 are weighed and dissolved bystirring in 90% of the batch quantity of purified water. The pH isadjusted to 7.5±0.1 with NaOH and/or HCl. Under yellow light or reducedlighting, the batch quantity of a compound of formula (I) as a stocksolution in ethanol and the additional quantity of ethanol necessary forthe batch are measured and added. Purified water is added to q.s. to100%. The mixture is stirred for five minutes to homogenize and thenfiltered through a sterilizing filter membrane into a sterile recipient.

[0091] Preferably, the above process is performed using glass, plasticor other non-metallic containers or containers lined with suchmaterials.

[0092] The invention has been described by reference to certainpreferred embodiments; however, it should be understood that it may beembodied in other specific forms or variations thereof without departingfrom its spirit or essential characteristics. The embodiments describedabove are therefore considered to be illustrative in all respects andnot restrictive, the scope of the invention being indicated by theappended claims rather than by the foregoing description.

What is claimed is:
 1. A composition for the treatment of dry eye andother disorders requiring the wetting of the eye in mammals comprising apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of one or more compounds of the following formula I:

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where: R is H or apharmaceutically acceptable cation, or CO₂R forms a pharmaceuticallyacceptable ester moiety; NR²R³, NR⁵R⁶ are the same or different andcomprise a free or functionally modified amino group; OR⁴ comprises afree or functionally modified hydroxy group; Hal is F, Cl, Br, or I;SR²⁰ comprises a free or functionally modified thiol group; R²¹ is H ora pharmaceutically acceptable cation, or COSR²¹ forms a pharmaceuticallyacceptable thioester moiety; A, B, C, D are the same or different andare C₁-C₅ alkyl, C₂-C₅ alkenyl, C₁₋₅ cyclopropyl, C₂-C₅ alkynyl, or aC₃-C₅ allenyl group; E is

where OR⁷ comprises a free or functionally modified hydroxy group;X=(CH₂)_(m) or (CH₂)_(m)O, where m=1-6; and Y=a phenyl ring optionallysubstituted with alkyl, halo, trihalomethyl, acyl, or a free orfunctionally modified hydroxy, amino, or thiol group; orX—Y=(CH₂)_(p)Y¹; where p=0-6; and

wherein: W=CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁸; where q=0-2, and R⁸=H, alkyl, or acyl; Z=H, alkyl,acyl, halo, trihalomethyl, or a free or functionally modified amino,thiol, or hydroxy group; and - - - =single or double bond; orX—Y=cyclohexyl.
 2. The composition of claim 1, wherein: R¹ is CO₂R,where R is H or an ophthalmically acceptable cationic salt, or CO₂Rforms an ophthalmically acceptable ester moiety; A, B, C, D are the sameor different and are CH₂CH₂, CH═CH, C≡C, or

E is

where R⁷ is H or CH₃; X is CH₂CH₂ or CH₂O; and Y phenyl, optionallysubstituted with halo, trifluoromethyl, or a free or functionalizedhydroxy group; or X—Y=cyclohexyl; or X—Y=Y¹,


3. The composition of claim 2, wherein the compound is:


4. The composition of claim 2, wherein the compound is:


5. The composition of claim 2, wherein the compound is:


6. The composition of claim 2, wherein the compound is:


7. The composition of claim 1 wherein the compound is selected from thegroup consisting of:


8. The composition of claim 1 wherein the composition is suitable fortopical administration to the eye.
 9. A method for the treatment of dryeye and other disorders requiring the wetting of the eye in mammalscomprising administering to an affected eye, a pharmaceuticallyeffective amount of one or more compounds according to formula I:

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where: R is H or apharmaceutically acceptable cation, or CO₂R forms a pharmaceuticallyacceptable ester moiety; NR²R³, NR⁵R⁶ are the same or different andcomprise a free or functionally modified amino group; OR⁴ comprises afree or functionally modified hydroxy group; Hal is F, Cl, Br, or I;SR²⁰ comprises a free or functionally modified thiol group; R²¹ is H ora pharmaceutically acceptable cation, or COSR²¹ forms a pharmaceuticallyacceptable thioester moiety; A, B, C, D are the same or different andare C₁-C₅ alkyl, C₂-C₅ alkenyl, C ₁₋₅ cyclopropyl, C₂-C₅ alkynyl, or aC₃-C₅ allenyl group; E is

where OR⁷ comprises a free or functionally modified hydroxy group;X=(CH₂)_(m) or (CH₂)_(m)O, where m=1-6; and Y=a phenyl ring optionallysubstituted with alkyl, halo, trihalomethyl, acyl, or a free orfunctionally modified hydroxy, amino, or thiol group; orX—Y=(CH₂)_(p)Y¹; where p=0-6; and

wherein: W=CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁸; where q=0-2, and R⁸=H, alkyl, or acyl; Z=H, alkyl,acyl, halo, trihalomethyl, or a free or functionally modified amino,thiol, or hydroxy group; and - - - =single or double bond; orX—Y=cyclohexyl.
 10. The method of claim 9, wherein the mammal is a humanand the compound is administered topically.
 11. The method of claim 9,wherein for the compound of formula I: R¹ is CO₂R, where R is H or anophthalmically acceptable cationic salt, or CO₂R forms an ophthalmicallyacceptable ester moiety; A, B, C, D are the same or different and areCH₂CH₂, CH═CH, C≡C, or

E is

where R⁷ is H or CH₃; X is CH₂CH₂ or CH₂O; and Y phenyl, optionallysubstituted with halo, trifluoromethyl, or a free or functionalizedhydroxy group; or X—Y=cyclohexyl; or X—Y=Y¹,


12. The method of claim 11, wherein the compound is:


13. The method of claim 11, wherein the compound is:


14. The method of claim 11, wherein the compound is:


15. The method of claim 11, wherein the compound is:


16. The method of claim 9, wherein the compound is selected from thegroup consisting of:


17. The method of claim 9 wherein the dry eye and other disordersrequiring the wetting of the eye is symptoms of dry eye associated withrefractive surgery.
 18. A compound of formula I:

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where: R is H or apharmaceutically acceptable cation, or CO₂R forms a pharmaceuticallyacceptable ester moiety; NR²R³, NR⁵R⁶ are the same or different andcomprise a free or functionally modified amino group; OR⁴ comprises afree or functionally modified hydroxy group; Hal is F, Cl, Br, or I;SR²⁰ comprises a free or functionally modified thiol group; R²¹ is H ora pharmaceutically acceptable cation, or COSR²¹ forms a pharmaceuticallyacceptable thioester moiety; A, B, C, D are the same or different andare C₁-C₅ alkyl, C₂-C₅ alkenyl, C₁₋₅ cyclopropyl, C₂-C₅ alkynyl, or aC₃-C₅ allenyl group; E is

where OR⁷ comprises a free or functionally modified hydroxy group;X=(CH₂)_(m) or (CH₂)_(m)O, where m=1-6; and Y=a phenyl ring optionallysubstituted with alkyl, halo, trihalomethyl, acyl, or a free orfunctionally modified hydroxy, amino, or thiol group; orX—Y=(CH₂)_(p)Y¹; where p=0-6; and

wherein: W=CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH=CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁸; where q=0-2, and R⁸=H, alkyl, or acyl; Z=H, alkyl,acyl, halo, trihalomethyl, or a free or functionally modified amino,thiol, or hydroxy group; and - - - =single or double bond; orX—Y=cyclohexyl.
 19. The compound of claim 18, wherein: R¹ is CO₂R, whereR is H or an ophthalmically acceptable cationic salt, or CO₂R forms anophthalmically acceptable ester moiety; A, B, C, D are the same ordifferent and are CH₂CH₂, CH═CH, C≡C, or

E is

where R⁷ is H or CH₃; X is CH₂CH₂ or CH₂O; and Y phenyl, optionallysubstituted with halo, trifluoromethyl, or a free or functionalizedhydroxy group; or X—Y=cyclohexyl; or X—Y=Y¹,


20. The compound of claim 18, wherein the compound is selected from thegroup consisting of:


21. The compound of claim 18, wherein the compound is selected from thegroup consisting of: